Evaluation of Mouse Hallucinations by fMRI

通过功能磁共振成像评估小鼠幻觉

• 批准号: 7714706
• 负责人: PAUL H PATTERSON
• 金额: $ 31.54万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-27 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7714706
• 关键词: Animal Model; Animals; Anxiety; Area; Auditory Hallucination; Behavior; Biological Assay; Brain; Characteristics; Cognitive; Delusions; Devices; Disease; Dose; Epidemiology; Evaluation; Functional Magnetic Resonance Imaging; Hallucinations; Hallucinogens; Human; Infection; Investigation; Magnetic Resonance Imaging; Measures; Mental disorders; Mothers; Motor; Mouse Strains; Mus; Neurons; Patients; Pregnancy; Procedures; Reporting; Research Personnel; Respiratory Tract Infections; Schizophrenia; Sensory; Series; Social Interaction; Societies; Somatosensory Cortex; Suicide; Symptoms; Testing; Violence; Visual; Work; awake; base; disorder risk; flexibility; mouse model; neuropathology; novel; novel strategies; novel therapeutics; offspring; prepulse inhibition; research study; success

DESCRIPTION (provided by applicant): Despite the impact on society, and the demonstrated utility of animal models for understanding disease, relatively few researchers work on animal models of mental illness such as schizophrenia. A major stumbling block is, how does one know if a mouse is schizophrenic? Although it is possible to measure behaviors related to the negative symptoms of schizophrenia such as deficits in social interaction, cognitive flexibility and sensory-motor gating, it is said to be impossible to evaluate the positive symptoms of schizophrenia, hallucinations and delusions. Thus, this disorder is often considered to be "uniquely human". We aim to test this assertion by developing an assay for a positive symptom of schizophrenia. We have developed an animal model with relevance for schizophrenia that is based on epidemiological findings that the risk for this disorder is strongly increased by maternal infection. The offspring of mice given a respiratory infection at mid-pregnancy display deficits in a series of behaviors relevant to schizophrenia. These include social interaction, prepulse inhibition, latent inhibition, interaction with a novel object, as well as increased anxiety under mildly stressful conditions. Moreover, these offspring display neuropathology that is characteristic of schizophrenia. We propose a novel approach towards animal studies of a positive symptom of schizophrenia. This will require a major advance with broad implications: establishing functional magnetic resonance imaging (fMRI) in awake mice. Using surrogate histological measures of neuronal activity, it appears that the mouse brain responds to hallucinogens in a manner similar to the human. Moreover, preliminary experiments indicate that at least one strain of mice can be adapted to the restraining device, allowing fMRI scanning. If this procedure can be established reliably, we will test the offspring of infected mothers for sensitivity to subthreshold doses of hallucinogens, as well as for spontaneous hallucinations, as defined by activity in the visual or somatosensory cortices in the absence of sensory input. Even partial success in this project could open up several new fields of investigation, attracting investigators into the important area of mouse models of mental illness. Auditory hallucinations are reported by 50-70% of schizophrenia patients, and they are often associated with acts of violence and suicide. Since the cause is unknown, an appropriate animal model of hallucination-like brain activity would be extremely useful in exploring novel therapeutic avenues.

描述（由申请人提供）：尽管对社会产生了影响，并且证明了动物模型用于理解疾病的实用性，但相对较少的研究人员从事精神疾病的动物模型（例如精神分裂症）的工作。一个主要的绊脚石是，如何知道小鼠是否是精神分裂症的？尽管可以衡量与精神分裂症的负面症状有关的行为，例如社交相互作用的缺陷，认知灵活性和感觉运动门控，但据说无法评估精神分裂症，幻觉和妄想的积极症状。因此，这种疾病通常被认为是“独特的人类”。我们的目的是通过开发精神分裂症阳性症状的测定法测定这一主张。我们已经开发了一种与精神分裂症相关的动物模型，该模型基于流行病学发现，即母亲感染会大大增加这种疾病的风险。小鼠的后代在中期处于患者中的呼吸道感染显示与精神分裂症相关的一系列行为中的缺陷。这些包括社交互动，预硫化，潜在抑制作用，与​​新物体的相互作用以及在轻度压力条件下的焦虑增加。此外，这些后代表现出精神分裂症的特征神经病理学。我们提出了一种新型的方法，以研究精神分裂症的积极症状。这将需要具有广泛影响的重大进展：在清醒小鼠中建立功能磁共振成像（fMRI）。使用神经元活性的替代组织学测量，看来小鼠脑以类似于人类的方式对致幻剂反应。此外，初步实验表明，至少一种小鼠可以适应限制装置，从而允许fMRI扫描。如果可以可靠地确定此过程，我们将测试感染母亲的后代，以使阈值剂量的幻觉剂量以及自发幻觉，这是在没有感觉输入的情况下视觉或体感皮质的活性所定义的。即使在该项目中的部分成功也可以开放一些新的调查领域，从而吸引研究人员进入小鼠模型的重要领域。 50-70％的精神分裂症患者报告了听觉幻觉，它们通常与暴力行为和自杀有关。由于原因尚不清楚，因此适当的幻觉样脑活动模型将在探索新型治疗途径方面非常有用。